Method of preparing 4-aminodiphenylamine

ABSTRACT

A method of producing 4-ADPA is disclosed wherein aniline or substituted aniline derivatives and nitrobenzene are reacted under suitable conditions to produce 4-nitrodiphenylamine or substituted derivatives thereof and/or 4-nitrosodiphenylamine or substituted derivatives thereof and/or their salts, either or both of which are subsequently reduced to produce 4-ADPA or substituted derivatives thereof. The 4-ADPA or substituted derivatives thereof can be reductively alkylated to produce p-phenylenediamine products or substituted derivatives thereof which are useful as antiozonants. A second embodiment of the invention is the tetrasubstituted ammonium salts or alkyl substituted diammonium salts of 4-nitrodiphenylamine, 4-nitrosodiphenylamine and the substituted derivatives thereof wherein each substituent of the tetrasubstituted ammonium ion is independently selected from the group consisting of alkyl, aryl and arylalkyl groups and each alkyl substituent of the alkyl substituted diammonium salt is independently selected.

CROSS REFERENCE TO BELATED APPLICATION

This application is a Rule 371 of PCT/US 92/02232, filed Mar. 27, 1992and a continuation-in-part of application Ser. No. 07/719,876, filedJun. 21, 1991, now U.S. Pat. No. 5,117,063.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to methods for preparing4-aminodiphenylamine (4-ADPA) and, more particularly, relates to amethod for preparing 4-ADPA wherein aniline is reacted with nitrobenzenein the presence of a base, and under conditions wherein the amount ofprotic material, e.g., water, is controlled, to produce a mixture richin the salt of 4-nitrodiphenylamine and/or the salt of4-nitrosodiphenylamine. The 4-nitrodiphenylamine and/or4-nitrosodiphenylamine salts can be isolated and subsequentlyhydrogenated or, alternatively, the reaction mixture itself ishydrogenated, to produce 4-ADPA in high yield. The present inventionalso relates to methods for preparing 4-ADPA intermediates as well as toalkylated p-phenylenediamine products useful as antioxidants.

2. Related Art

It is known to prepare 4-ADPA by way of a nucleophilic aromaticsubstitution mechanism, wherein an aniline derivative replaces halide.This method involves preparation of a 4-ADPA intermediate, namely4-nitrodiphenylamine (4-NDPA) followed by reduction of the nitro moiety.The 4-NDPA is prepared by reacting p-chloronitrobenzene with an anilinederivative, such as formanilide or an alkali metal salt thereof, in thepresence of an acid acceptor or neutralizing agent, such as potassiumcarbonate, and, optionally, utilizing a catalyst. See, for example, U.S.Pat. Nos. 4,187,248; 4,683,332; 4,155,936; 4,670,595; 4,122,118;4,614,817; 4,209,463; 4,196,146; 4,187,249; 4,140,716. This method isdisadvantageous in that the halide that is displaced is corrosive to thereactors and appears in the waste stream and must therefore be disposedof at considerable expense. Furthermore, use of an aniline derivativesuch as formanilide, and use of p-chloro-nitrobenzene, requiresadditional manufacturing equipment and capabilities to produce suchstarting materials from aniline and nitrobenzene, respectively.

It is also known to prepare 4-ADPA from the head-to-tail coupling ofaniline. See, for example, G.B. 1,440,767 and U.S. Pat. No. 4,760,186.This method is disadvantageous in that the yield of 4-ADPA is notacceptable for a commercial process. It is also known to decarboxylate aurethane to produce 4-NDPA. See U.S. Pat. No. 3,847,990. However, suchmethod is not commercially practical in terms of cost and yield.

It is known to prepare 4-ADPA by hydrogenatingp-nitrosodiphenylhydroxylamine which can be prepared by catalyticdimerization of nitrosobenzene utilizing, as a reducing agent, aliphaticcompounds, benzene, naphthalene or ethylenically unsaturated compounds.See, for example, U.S. Pat. Nos. 4,178,315 and 4,404,401. It is alsoknown to prepare p-nitrosodiphenylamine from diphenylamine and an alkylnitrate in the presence of excess hydrogen chloride. See, for example,U.S. Pat. Nos. 4,518,803 and 4,479,008.

It is also known to produce 4-nitrosodiphenylamine by reactingacetanilide and nitrobenzene in DMSO in the presence of sodium hydroxideand potassium carbonate at 80° C. for 5 hours. See Ayyangar et al.,Tetrahedron Letters, Vol. 31, No. 22, pp. 3217-3220 (1990). See also,Wohl, Chemische Berichte, 36, p. 4135 (1903) and Chemische Berichte, 34,p. 2442 (1901). However, the yield of 4-nitrosodiphenylamine is low andis therefore not commercially practical. Furthermore, such methodrequires utilization of an aniline derivative, namely, acetanilide, andtherefore increases the cost of the starting materials.

The process of the present invention does not include a halide sourceand therefore eliminates the expensive halide removal from the wastestream. In addition, the process of the present invention is much lessexpensive in terms of manufacturing costs, as well as the cost of rawmaterials, because instead of the derivatives of aniline andnitrobenzene, the present method utilizes aniline and nitrobenzenedirectly.

SUMMARY OF THE INVENTION

The present invention is directed to a method of preparing 4-ADPAintermediates or the substituted derivatives thereof, e.g.,4-nitrodiphenylamine (4-NDPA) and the salts thereof, and/or4-nitrosodiphenylamine (p-NDPA or 4-NODPA) and/or the salts thereof,wherein aniline or substituted aniline derivatives and nitrobenzene arebrought into reactive contact in a suitable solvent system, and thenreacted in the presence of a base and under conditions wherein theamount of protic material, such as water, is controlled. The resultingreaction mixture is rich in 4-ADPA intermediates or the substitutedderivatives thereof, including the 4-nitrodiphenylamine and/or4-nitrosodiphenylamine salts. The process can be utilized according tothe teachings of the present invention to produce a high yield of the4-nitroso product (p-nitrosodiphenylamine and its salt) with little orno 4-nitro product. The 4-nitroso reaction product mixture can then behydrogenated directly, or the 4-nitroso product can then be isolated andsubsequently hydrogenated, to produce 4-ADPA in high yield. Similarly,the 4-nitro product (4-nitrodiphenylamine and its salt) can be producedin high yield with little or no 4-nitroso product, and the 4-nitroproduct, or the isolated 4-nitro product, can be hydrogenated to produce4-ADPA in high yield. Alternatively, the 4-nitro and 4-nitroso productsare both produced and are not isolated but the reaction mixture ishydrogenated directly to produce 4-ADPA. The resulting 4-ADPA can beutilized to prepare alkylated products of p-phenylenediamine, whichproducts are useful as antioxidants and antiozonants. Alternatively, the4-ADPA intermediates can be reduced and the reduced material alkylatedin the same reaction vessel utilizing a ketone as a solvent.

In one embodiment of the invention, the amount of protic materialpresent during the reaction of aniline or substituted anilinederivatives and nitrobenzene is controlled by having a desiccant presentduring the reaction. In another embodiment, the amount of proticmaterial present during the reaction of aniline or substituted anilinederivatives and nitrobenzene is controlled by continuously removingprotic material by distillation.

The present invention is further directed to the tetrasubstitutedammonium salts or alkyl substituted diammonium salts of4-nitrodiphenylamine, 4-nitrosodiphenylamine and the substitutedderivatives thereof wherein each substituent of the tetrasubstitutedammonium salt is independently selected from the group consisting ofalkyl, aryl and arylalkyl groups and each alkyl substituent of the alkylsubstituted diammonium salt is independently selected.

DETAILED DESCRIPTION OF THE INVENTION

The subject method for producing 4-ADPA intermediates involves the stepsof:

a) bringing aniline or substituted aniline derivatives and nitrobenzeneinto reactive contact in a suitable solvent system;

b) reacting the aniline or substituted aniline derivatives andnitrobenzene in a confined zone, such as a reactor, at a suitabletemperature and in the presence of a suitable base and a controlledamount of protic material, such as water, to produce4-nitrodiphenylamine or substituted derivatives thereof and its saltand/or 4-nitrosodiphenylamine or substituted derivatives thereof and itssalt.

For producing 4-ADPA or substituted derivatives thereof, the subjectmethod includes the following step:

c) reducing the 4-nitrosodiphenylamine or substituted derivativesthereof and its salt and/or the 4-nitrodiphenylamine or substitutedderivatives thereof and its salt to produce 4-ADPA.

For producing alkylated p-phenylenediamines or substituted derivativesthereof, the subject method includes the step of:

d) reductively alkylating the 4-ADPA or substituted derivatives thereofof Step c).

As utilized herein, the term "4-ADPA intermediates" means4-nitrodiphenylamine, 4-nitrosodiphenylamine (also referred to asp-nitrosodiphenylamine), the substituted derivatives thereof and thesalts thereof. Thus, reference to "one or more 4-ADPA intermediates"refers to one or both of the neutral compounds, i.e., those that are notin the form of a salt, and/or the salt of one or both of such compounds.The salt is produced in the reaction mixture from reaction of the4-nitro and/or 4-nitroso products with the base. Thus, the reactionmixture produced in the method of the present invention can include oneof the compounds or salts or any combination thereof depending on thespecific reaction conditions selected.

The molar ratio of aniline or substituted aniline derivatives tonitrobenzene can vary from a large excess of nitrobenzene to a largeexcess of aniline or substituted aniline derivative. Preferably, thereaction is conducted utilizing an excess of aniline or substitutedaniline derivative. The ratio of 4-nitro to 4-nitroso produced in thereaction of the present invention can be controlled by varying the ratioof aniline to nitrobenzene. For example, the higher the ratio of anilineto nitrobenzene, the higher the ratio of 4-nitroso to 4-nitro.Conversely, the higher the ratio of nitrobenzene to aniline, the higherthe ratio of 4-nitro to 4-nitroso.

As used herein, the term "substituted aniline derivatives" means anilinecontaining one or more electron withdrawing or electron releasingsubstituents on the aromatic ring. Applicable substituents include, butare not limited to, halides, --NO₂, --NH₂, alkyl groups, alkoxy groups,--SO₃, --COOH and aryl, aralkyl or alkaryl groups containing at leastone --NH₂ group. Halides are selected from the group consisting ofchloride, bromide and fluoride. The preferred alkyl and alkoxy groupscontain from 1 to about 6 carbon atoms. The preferred aryl, aralkyl andalkaryl groups contain from about 6 to about 18 carbon atoms. Examplesof substituted aniline derivatives include, but are not limited to,2-methoxyaniline, 4-methoxyaniline, 4-chloroaniline, p-toluidine,4-nitroaniline, 3-bromoaniline, 3-bromo-4-aminotoluene, p-aminobenzoicacid, 2,4-diaminotoluene, 2,5-dichloroaniline, 1,4-phenylene diamine,4,4'-methylene dianiline, 1,3,5-triaminobenzene and mixtures thereof.

Aniline or substituted aniline derivatives can be added directly or canbe formed in situ by addition of a compound that will form aniline orthe corresponding aniline derivative under the conditions present in thereaction system.

Azobenzene is also produced in this reaction in variable quantitiesdepending on the reaction conditions. One way of controlling azobenzeneproduction is through the ratio of aniline to nitrobenzene. Thus, asthis ratio is increased, the amount of azobenzene generally decreases.As discussed below, and as illustrated in the Examples set forth below,other variables, such as the amount of base and oxygen, can also affectthe amount of azobenzene produced. Thus, utilizing the teachings of thepresent invention, one skilled in the art can conduct the reaction ofthe present invention to control the amount of azobenzene that isproduced.

Suitable solvent systems include, but are not limited to, solvents suchas, for example, dimethylsulfoxide, N-methylpyrrolidone,dimethylformamide, aniline, pyridine, nitrobenzene, nonpolar hydrocarbonsolvents such as toluene and hexane, ethyleneglycol dimethyl ether,diisopropyl ethylamine, and the like, as well as mixtures thereof.Preferably, aniline or substituted aniline derivative is used in excessin the reaction as stated above, and the aniline or substituted anilinederivative in excess of the molar amount of nitrobenzene serves as thesolvent. As described in more detail below, solvent mixtures can beutilized wherein one or more of the suitable solvents and anothersolvent, such as a controlled amount of a protic solvent, e.g.,methanol, are combined.

Suitable bases include, but are not limited to, organic and inorganicbases such as, for example, alkali metals, such as sodium metal, alkalimetal hydrides, hydroxides and alkoxides, such as sodium hydride,lithium hydroxide, sodium hydroxide, cesium hydroxide, potassiumhydroxide, potassium t-butoxide, and the like, including mixturesthereof. Other acceptable base materials include, but are not limitedto, phase transfer catalysts in conjunction with a suitable base sourcesuch as tetrasubstituted ammonium hydroxides wherein each substituent isindependently selected from alkyl, aryl or arylalkyl groups wherein thealkyl, aryl and arylalkyl groups preferably have 1 to about 18 carbonatoms, including tetraalkylammonium hydroxides, e.g.,tetramethylammonium hydroxide, aryl, trialkyl ammonium hydroxides, e.g.,phenyltrimethylammonium hydroxide, arylalkyl, trialkylammoniumhydroxides, e.g., benzyl trimethylammonium hydroxide, alkyl substituteddiammonium hydroxides, e.g., bis-dibutylethyl hexamethylene diammoniumhydroxide, and other combinations of phase transfer catalysts andsuitable bases such as suitable bases in conjunction with aryl ammoniumsalts, crown ethers and the like, and amine bases, such as lithiumbis(trimethylsilyl) amide, and the like, including mixtures thereof.Preferred materials (bases) for use as bases are tetraalkylammoniumhydroxides such as tetramethylammonium hydroxide. Preferably, the baseis added to the aniline or substituted aniline derivative to produce amixture which is then combined with the nitrobenzene. Alternatively,.the base can be added after the aniline or substituted anilinederivative and nitrobenzene have been combined. Addition of materialscan be above or below surface addition. The amount of base utilized inthe present process can vary over a wide range. For example, thereaction can be conducted in a manner which is limiting in base or thereaction can be conducted in a manner which is limiting in nitrobenzeneor aniline or substituted aniline derivative depending, among otherfactors, on the desired degree of minimization of azobenzene.

The reaction is conducted at a suitable temperature which can vary overa wide range. For example, the temperature can fall within a range offrom about -10° C. to about 150° C., such as from about 0° C. to about100° C., preferably from about 10° C. to about 90° C. A most preferredtemperature for conducting the reaction of the present invention is fromabout 60° C. to about 80° C., such as at 75° C. Where aniline isutilized as the solvent under aerobic reaction conditions, as thetemperature of the reaction increases, the amount of azobenzene producedincreases. However, where the reaction is conducted in aniline underanaerobic conditions, higher temperatures do not necessarily increasethe amount of azobenzene. Where production of azobenzene is not aproblem, higher temperatures will be suitable. However, where it isdesired to minimize the amount of azobenzene, lower temperatures oranaerobic reaction conditions are more suitable. Alternatively, tominimize the amount of azobenzene while conducting the reaction athigher temperatures, a solvent other than aniline can be used and theratio of aniline or substituted aniline derivative to nitrobenzene canbe controlled.

Control of the amount of protic material present in the reaction isimportant. Generally, when the reaction is conducted in aniline, waterpresent in the reaction in an amount greater than about 4% H₂ O, (basedon volume of the reaction mixture) inhibits the reaction of the anilinewith the nitrobenzene to an extent where the reaction is no longersignificant. Reducing the amount of water to below the 4% level causesthe reaction to proceed in an acceptable manner. Whentetramethylammonium hydroxide is utilized as a base with aniline as thesolvent, as the amount of water is reduced further, e.g., down to about0.5% based on the volume of the reaction mixture, the total amount of4-nitrodiphenylamine and 4-nitrosodiphenylamine and/or salts thereofincreases with some loss in selectivity so that more2-nitrodiphenylamine is produced but still in minor amounts. Thus, thepresent reaction could be conducted under anhydrous conditions. A"controlled amount" of protic material is an amount up to that whichinhibits the reaction of aniline with nitrobenzene, e.g., up to about 4%H₂ O based on the volume of the reaction mixture when aniline isutilized as the solvent. The upper limit for the amount of proticmaterial present in the reaction varies with the solvent. For example,when DMSO is utilized as the solvent and tetramethylammonium hydroxideis utilized as the base, the upper limit on the amount of proticmaterial present in the reaction is about 8% H₂ O based on the volume ofthe reaction mixture. When aniline is utilized as a solvent with thesame base, the upper limit is 4% H₂ O based on the volume of thereaction mixture. In addition, the amount of protic material toleratedwill vary with type of base, amount of base, and base cation, used inthe various solvent systems. However, it is within the skill of one inthe art, utilizing the teachings of the present invention, to determinethe specific upper limit of the amount of protic material for a specificsolvent, type and amount of base, base cation and the like. The minimumamount of protic material necessary to maintain selectivity of thedesired products will also depend on the solvent, type and amount ofbase, base cation and the like, that is utilized and can also bedetermined by one skilled in the art.

Since the amount of protic material present in the reaction isimportant, it is possible to reduce the amount of protic materialpresent as much as possible and then add back to the reaction thedesired amount, e.g., 0.5 vol. % when aniline is used as the solvent.Protic materials that can be utilized to add back to the reaction areknown to those skilled in the art and include, but are not limited to,water, methanol and the like. Methods for measuring the amount of proticmaterial and for reducing the amount of protic material as much aspossible are well known in the art. For example, the amount of waterpresent in certain reagents can be determined by utilizing aKarl-Fischer apparatus, and the amount of water can be reduced throughdistillation and/or drying under reduced pressure, drying in thepresence of P₂ O₅ and other agents, azeotropic distillation utilizing,for example, aniline, and the like, including combinations thereof.

In one embodiment for controlling the amount of protic material duringthe reaction of aniline or substituted aniline derivatives andnitrobenzene, a desiccant is added so as to be present during thereaction of aniline or substituted aniline derivative and nitrobenzene.For example, when the protic material is water, the desiccant removeswater present during the reaction of aniline or substituted anilinederivatives and nitrobenzene and results in higher conversion ofnitrobenzene and yields of 4-nitrodiphenylamine and4-nitrosodiphenylamine or substituted derivatives thereof. As usedherein, desiccant is a compound present during the reaction of anilineor substituted aniline derivatives and nitrobenzene in addition to thesuitable base used. Examples of suitable desiccants include, but are notlimited to, anhydrous sodium sulfate, molecular sieves such as types 4A,5A and 13X available from the Union Carbide Corporation, calciumchloride, tetramethyl ammonium hydroxide dihydrate, anhydrous bases suchas KOH and NaOH, and activated alumina.

In another embodiment for controlling the amount of protic materialduring the reaction of aniline or substituted aniline derivatives andnitrobenzene, protic material is continuously removed from the reactionmixture by distillation. When the protic material is water, thepreferred method involves continuous azeotropic distillation of waterutilizing the water/aniline azeotrope. The continuous distillation ofprotic material is the currently preferred method for controlling theamount of protic material present during the reaction of aniline orsubstituted aniline derivatives and nitrobenzene. The continuous removalof protic material allows the use of lower amounts of base in thereaction of aniline or substituted aniline derivatives and nitrobenzenewhile achieving very high conversion of nitrobenzene and excellentyields of 4-nitrodiphenylamine and 4-nitrosodiphenylamine and/or saltsthereof or substituted derivatives thereof.

The reaction can be conducted under aerobic or anaerobic conditions.Under aerobic conditions, the reaction is conducted essentially asdescribed above in a reaction zone which is exposed to oxygen, usuallyby exposure to air. Under aerobic conditions, the pressure at which thereaction is conducted can vary and the optimal pressure, as well as theoptimal combination of pressure and temperature/pressure conditions, areeasily determined by one skilled in the art. For example, the reactioncan be conducted at room temperature and at a pressure ranging fromabout 10 psig to about 250 psig, such as from about 14 to about 150psig. Under anaerobic conditions, the reaction can be conducted atatmospheric pressure or reduced or increased pressures, in the presenceof a neutral gas such as, for example, nitrogen or argon. Optimalconditions for a particular set of reaction parameters, such astemperature, base, solvent and the like, are easily determined by oneskilled in the art utilizing the teachings of the present invention. Ithas been observed that less azobenzene is produced when the reaction isconducted anaerobically with aniline as the solvent. It has also beenobserved that less azobenzene is produced when the reaction is conductedaerobically with DMSO, and other similar solvents, as the solvent.

The 4-nitrodiphenylamine or substituted derivatives thereof and/or4-nitrosodiphenylamine or substituted derivatives thereof and/or theirsalts can be reduced to 4-ADPA or substituted derivatives thereof. Theneutral compounds can be generated from the salts utilizing water and/oran acid. See, for example, Example 1D. Alternatively, the salts can bereduced as shown in Example 1A. This reduction can be carried out by anyof many known reductive processes, such as using a hydride source, e.g.,sodium borohydride in conjunction with palladium- or platinum-on-carboncatalyst. Preferably, this reduction is conducted by a catalyticreduction wherein hydrogenation is effected under hydrogen pressure inthe presence Of platinum- or palladium-on-carbon, nickel, and the like.This hydrogenation process is described in detail in "CatalyticHydrogenation in Organic Synthesis". P. N. Rylander, Academic Press, NewYork, p. 299 (1979), which is hereby incorporated herein by reference.The hydrogenation can be conducted in a variety of solvents including,but not limited to, toluene, xylene, aniline, 4-ADPA, water and mixturesthereof. Preferably, the hydrogenation is conducted utilizing aplatinum-on-carbon or palladium-on-carbon catalyst in a suitable solventsuch as, for example, either toluene, 4-ADPA, xylene or aniline,mixtures thereof, or mixtures which include water as the solvent and ahydrogen pressure of from 100 psig H₂ to about 340 psig H₂ at atemperature of about 80° C.

Reductive alkylation of 4-ADPA to produce antiozonants can be conductedby any one of several well known methods. See, for example, U.S. Pat.No. 4,900,868. Preferably, 4-ADPA and a suitable ketone or aldehyde arereacted in the presence of hydrogen and platinum on carbon as catalyst.Suitable ketones include methylisobutyl ketone (MIBK), acetone,methylisoamylketone and 2-octanone. It should be noted that reduction ofthe 4-ADPA intermediates and alkylation of the reduced material can beconducted in the same reaction vessel utilizing the ketone as a solvent.See, for example, U.S. Pat. No. 4,463,191, and Banerjee et al, J. Chem.Soc. Chem. Comm. 18, 1275-76 (1988).

Contemplated equivalents of the reactants and reagents set forth aboveare reactants and reagents otherwise corresponding thereto and havingthe same general properties wherein one or more of the various groups,e.g., NO₂, are simple variations. In addition, where a substituent isdesignated as, or can be, a hydrogen, the exact chemical nature of asubstituent which is other than hydrogen at that position is notcritical so long as it does not adversely affect the overall activityand/or synthesis procedure.

The chemical reactions described above are generally disclosed in termsof their broadest application to the method of this invention.Occasionally, the reaction conditions may not be applicable asspecifically described to each reactant and reagent within the disclosedscope. For example, certain suitable bases may not be as soluble in onesolvent as they are in other solvents. The reactants and reagents forwhich this occurs will be readily recognized by those skilled in theart. In all such cases, either the reactions can be successfullyperformed by conventional modifications known to those skilled in theart, e.g., by appropriate adjustments in temperature, pressure and thelike, by changing to alternative conventional reagents such as othersolvents or other bases, by routine modification of reaction conditions,and the like, or other reactions disclosed herein or otherwiseconventional, will be applicable to the method of this invention. In allpreparative methods, all starting materials are known or are readilypreparable from known starting materials.

Without further elaboration, it is believed that one skilled in the artcan, using the preceding description, utilize the present invention toits fullest extent. The following preferred specific embodiments are,therefore, to be construed as merely illustrative, and not limitative ofthe remainder of the disclosure in any way whatsoever.

All reagents were used as received except that the bases and solventswere dried as described hereinafter. Unless indicated otherwise, allyields were determined by HPLC according to the following method.

Materials and Methods

Aniline or substituted aniline derivatives and nitrobenzene were reagentgrade and were used without further purification. Solvents werepurchased from Aldrich Chemical and were anhydrous grade. Thetetramethylammonium hydroxide was purchased as the pentahydrate. Thesolid was dried in a desiccator over P₂ O₅ under vacuum for several daysbefore use. Titration of the resulting solid showed the dried materialto be the dihydrate.

HPLC Assay: Reverse phase HPLC was used to analyze the reactionmixtures. A 5 μm Beckman/Altex Ultrasphere-ODS (4.6×150 mm) column wasemployed using a ternary gradient pump system.

    ______________________________________                                        Elution Gradient                                                                      Flow Rate                                                             Time (min)                                                                            (mL/Min)  % Water   % ACN   % MeOH                                    ______________________________________                                        0       1.5       90        10       0                                        12.0    1.5       63        30       8                                        12.1    1.5       60        20      20                                        15      1.5       60        20      20                                        35      1.5       10        45      45                                        40      1.5       10        45      45                                        41      1.5       90        10       0                                        50      1.5       90        10       0                                        ______________________________________                                    

Example 1

A) This example illustrates a neat reaction of aniline and nitrobenzeneunder aerobic conditions at room temperature to generate 4-NDPA andp-nitrosodiphenylamine (p-NDPA) products. The reaction mixture was thenhydrogenated directly to generate 4-ADPA.

A 500 mL three-necked round bottom flask was equipped with a magneticstir bar. The reaction vessel was charged with 196 mL of aniline andnitrobenzene (4.3 mL, 42 mmole). To the stirred reaction mixture wasadded tetramethylammonium hydroxide dihydrate (17.7 grams, 140 mmoles)as a solid. The reaction was shown to have consumed nearly all thenitrobenzene after two hours, however, the reaction was allowed to stirfor 18 hours. After this time >99% of the nitrobenzene was consumed.HPLC analysis of the reaction mixture indicated the following yields ofproducts based on nitrobenzene: 4-NDPA (6.4 mmole, 1.37 g, 15%). p-NDPA(30.6 mmole, 6.1 g, 73%), 2-NDPA (0.3 mmole, 0.064 g, 0.7%), azobenzene(3.6 mmole, 0.65 g, 8.5%), phenazine (0.8 mmole, 0.14 g, 1.9%).phenazine-N-oxide (0.3 mmole, 0.05 g, 0.7%).

Water (16 ml) was added to the mixture and the entire reaction was thencharged into a 300 cc autoclave for hydrogenation. A 1% Pt/carboncatalyst (0.5 grams dry weight) was added to the autoclave. The reactionmixture was heated to 80° C. under 150 psig of H₂. Hydrogen uptake wascomplete within 30 minutes. HPLC analysis indicated that 35.9 mmole of4-ADPA was produced which corresponds to a 97% yield based on moles of4-NDPA and p-NDPA.

B) This is an example of the reaction of aniline and nitrobenzene atroom temperature in dimethylsulfoxide under anaerobic conditions.

A 25 mL round bottom flask was charged with 4 mL of DMSO, aniline, (200μL, 1.9 mmole) and tetramethylammonium hydroxide dihydrate (330 mg, 2.5mmole) under argon. The reaction was allowed to proceed at roomtemperature for 4 hours. Conversion of nitrobenzene was 68%. HPLCanalysis indicated the following yields based on nitrobenzene. 4-NDPA(30.5%), p-NDPA (33.6%), azobenzene (2.6%),. azoxybenzene (trace).

C) This is an example of a neat reaction between aniline andnitrobenzene at room temperature under anaerobic conditions.

A 25 mL round-bottom flask was charged with aniline (1.8 mL) andnitrobenzene (0.02 mL, 0.19 mmole) in a controlled atmosphere glove boxfilled with argon. To this solution was added tetramethylammoniumhydroxide dihydrate (330 mg, 2.5 mmole). All the nitrobenzene wasconsumed after several hours. HPLC analysis indicated the followingyields based on nitrobenzene: 4-NDPA 10%. p-NDPA 76%, azobenzene 7%, andphenazine 5%.

D) This is an example of the reaction between aniline and nitrobenzeneat room temperature in DMSO under aerobic conditions. This example alsoillustrates generation of 4-NDPA and p-NDPA from its salts utilizingwater and acid.

The reaction mixture contained aniline (200 μL, 2.1 mole) andnitrobenzene (200 μL, 1.9 mmole) in 4 mL of DMSO. Tetramethylammoniumhydroxide dihydrate (330 mg, 2.5 mmole)was added in one portion. Thereaction was allowed to stir for 18 hours after which time 80% of thenitrobenzene had been consumed. The reaction was dumped into 200 mL ofwater which caused the immediate precipitation of 4-NDPA. The solutionwas cooled on ice for several hours and the product was filtered off anddried at 100° C. The filtrate was treated with glacial acetic acid untilthe pH was neutral which caused the precipitation of p-NDPA. Theprecipitate was filtered and dried at 100° C. Isolated yields based onnitrobenzene consumed: 4-NDPA (66%), p-NDPA (29%).

E) This is an example of the reaction of aniline and nitrobenzene inDMSO at 80° C. under aerobic conditions.

A 250 mL round-bottom flask was charged with aniline (0.05 mole, 4.6 g),nitrobenzene (0.05 mole, 6.1 g) and 75 mL of DMSO. Tetramethylammoniumhydroxide dihydrate (0.2 mole, 25.44 g) was added to the solution in oneportion. The reaction mixture was heated to 80° C. in an oil bath andmaintained at that temperature for 5 hours. The reaction was analyzed byHPLC. Yields based on nitrobenzene; 4-NDPA (35%), p-NDPA (51%),azobenzene (3.1%).

F) This is an example of the reaction of aniline and nitrobenzene in DMFunder aerobic conditions.

Aniline (200 μL, 2.1 mmole) and nitrobenzene (200 μL, 1.9 mmole) wasdissolved in 5 mL of DMF. Tetramethylammonium hydroxide dihydrate (1.0g, 7.8 mmole) was added to the reaction. The reaction was allowed tostir for 2 hours during which time 39% of the nitrobenzene was consumed.Yields based on nitrobenzene consumed: 4-NDPA 99%, p-NDPA trace.

Example 2

This example illustrates that the reaction of the present invention canbe conducted over a range of temperatures. Four identical reactions wereprepared in the following manner and were run at 0°, 23°, 50° and 80° C.in the air. A 50 mL round-bottom flask was charged with 49 mL of anilineand nitrobenzene (1.0 mL, 9.5 mmole). Tetramethylammonium hydroxidedihydrate (4.40 g, 34.6 mmole) was added and the reaction was allowed toproceed for 5 hours. Product yields were determined by HPLC analysis andare based on moles nitrobenzene consumed. Selectivity is the ratio ofthe moles of product generated and the moles of nitrobenzene consumed.Yield is conversion times selectivity.

                  TABLE 1                                                         ______________________________________                                                 Nitrobenzene          %       %                                      Temp. °C.                                                                       Conversion Products   Selectivity                                                                           Yield                                  ______________________________________                                         0       52%        p-NDPA     34      18                                                         4-NDPA     18      9.3                                                        2-NDPA     2.2     1.0                                                        phenazine  0.6     0.3                                    23       73%        p-NDPA     71      51                                                         4-NDPA     12      8.5                                                        azobenzene 17      12                                                         phenazine          trace                                                      phenazine-         trace                                                      N-oxide                                                   50       98%        p-NDPA     88      86                                                         4-NDPA     7.8     7.6                                                        2-NDPA     1.7     1.6                                                        azobenzene*                                                                              22      21                                     80       100%       p-NDPA     89      89                                                         4-NDPA     7       7                                                          2-NDPA     2       2                                                          azobenzene*                                                                              55      55                                     ______________________________________                                         *The majority of azobenzene is produced presumably through oxidative          coupling of aniline. See D. T. Sawyer paper.                             

Example 3

This example illustrates that control of the amount of protic materialpresent in the reaction is important. Four identical reactions were runexcept the amount of water added to the mixture was varied to include 0,10, 50, and 100 μL. Thus aniline (2 mL) and amount of water added to themixture was varied to include 1, 10, 50, and 100 μL. Thus aniline (2 mL)and nitrobenzene (2 mL) were charged into a 25 mL round-bottom flask andvarious amounts of water were added. Tetramethylammonium hydroxidedihydrate (330 mg, 2.5 mmole) was added in one portion. The reactionswere allowed to run in the air at room temperature and were sampledafter 16 hours. An identical set of reactions was also run wheremethanol was added instead of water.

                  TABLE 2                                                         ______________________________________                                                                           Yield                                                          Ratio mmole    (mmole)                                    Volume (μL)                                                                          %         4-NDPA + p-NDPA/                                                                             4-NDPA +                                   Water Added                                                                             Water*    2-NDPA + Phenazine                                                                           p-NDPA                                     ______________________________________                                         0        2.2       6.2            0.83                                       10        2.45      8.5            0.68                                       50        3.45      11.5           0.18                                       100       4.7       5.0            0.05                                       Volume (μL)                                                                Methanol  %                                                                   Added     Methanol*                                                           10        0.25      8.8            0.67                                       50        1.25      16             0.57                                       100       2.5       35             0.42                                       ______________________________________                                         *The % water and methanol is by volume. In the case when no water was         added the water present in the reaction was introduced from the               tetramethylammonium hydroxide dihydrate.                                 

Example 4

This example illustrates that various solvents can be utilized in thepractice of the method of this invention to produce 4-NDPA and/or p-NDPAproducts. The reactions set forth in Table 3 were conducted as inExample 1 as indicated, except that the solvent of Example 1 was changedto that indicated in the table.

                  TABLE 3                                                         ______________________________________                                        Solvent          Reaction Conditions                                          ______________________________________                                        N-methyl-2-pyrrolidone                                                                         1D                                                           DMSO/THF         1B                                                           pyridine         1D                                                           ______________________________________                                    

Example 5

This example illustrates various bases which can be utilized in themethod of the present invention to produce 4-NDPA and/or p-NDPAproducts. The reactions set forth in Table 4 were conducted as inExample 1 as indicated except that the base of Example 1 was changed tothat indicated in the table.

                  TABLE 4                                                         ______________________________________                                        Base                Reaction Conditions                                       ______________________________________                                        Na metal            1D                                                        NaH                 1D                                                        NaOH                1D                                                        KOH                 1D                                                        Potassium t-butoxide                                                                              1D                                                        Lithium bis(trimethylsilyl)amide                                                                  1B, 1D                                                    NaOH/K.sub.2 CO.sub.3                                                                             1D, 1F                                                    ______________________________________                                    

Example 6

This example illustrates the unexpected increase in selectivity andnitrobenzene conversion utilizing the method of the present invention ascompared to the method disclosed in Ayyangar et al.

The reaction of acetanilide, nitrobenzene, NaOH, and K₂ CO₃ in DMSO wasrun according to the procedure described by Ayyangar et al. TetrahedronLetters, Vol. 31, No. 22, pp 3217-3220 (1990). Analysis of this reactionby HPLC indicated 37% of the nitrobenzene was converted and thefollowing yields based on nitrobenzene, were achieved. 4-NDPA (6%),p-NDPA (4.5%), azobenzene (0.7%).

In comparison, when the reaction is conducted according to the teachingsof the present invention, the conversions of nitrobenzene andselectivities to the desired products are greatly increased. Forexample, conducting the reaction as described in Example 1D, aniline(0.05 mole), nitrobenzene (0.05 mole) and tetramethylammonium hydroxidedihydrate (0.2 mole) were mixed in 75 mL of DMSO. The reaction wasstirred at room temperature for 5 hours after which time the reactionwas analyzed by HPLC chromatography giving the following results.Nitrobenzene conversion was (85%). Yield based on nitrobenzene: 4-NDPA(18%), p-NDPA (51%) azobenzene (3%).

The reaction of acetanilide and nitrobenzene was also run at roomtemperature. Thus, acetanilide (0.05 mole), nitrobenzene (0.05 mole),NaOH (0.2 mole) and K₂ CO₃ were dissolved in 75 mL of DMSO. The reactionwas stirred for 5 hours at room temperature (23° C.). Analysis of thereaction showed no conversion of nitrobenzene and no products detected.

Example 7

This example illustrates how the ratio of p-NDPA/4-NDPA can becontrolled by the ratio of aniline/nitrobenzene.

Aniline and nitrobenzene were reacted at various ratios, while the totalreaction volume and the amount of tetramethylammonium hydroxidedihydrate were held constant. Thus, in a typical reaction illustratingan aniline/nitrobenzene volume ratio of 1, aniline (2 mL) andnitrobenzene (2 mL) were charged into a 25 mL round-bottom flask.Tetramethylammonium hydroxide dihydrate (330 mg, 2.5 mmole) was addedand the reaction was allowed to proceed at room temperature in air for14 hours. The reactions were then analyzed by HPLC.

                  TABLE 5                                                         ______________________________________                                        Volume Ratio    Ratio                                                         Aniline/Nitrobenzene                                                                          p-NDPA/4-NDPA                                                 ______________________________________                                        0.33            0.1                                                           1               0.1                                                           10              4                                                             50              6                                                             ______________________________________                                    

Example 8

This example illustrates the effect that the amount of protic materialpresent in or added to the reaction has on the extent of conversion andyields of 4-NDPA and p-NDPA.

The amount of water added to a reaction of aniline, nitrobenzene andtetramethylammonium hydroxide dihydrate in DMSO was varied from zero to500 μL (0, 50, 150, 300, 500 μL) while keeping the total reaction volumeconstant. Thus, a typical reaction contained aniline, (200 μL, 2.1mmole), nitrobenzene (200 μL, 1.9 mmole), tetramethylammonium hydroxidedihydrate (330 mg, 2.5 mmole) and water (50 μL) in 3.55 mL of anhydrousDMSO. The reaction was allowed to react aerobically at room temperature24 hours after which time it was sampled and subjected to HPLC analysis.

                  TABLE 6                                                         ______________________________________                                        Volume (μL)                                                                         %        % Conversion                                                                              Yield (mmole)                                   Water Added                                                                            Water    Nitrobenzene                                                                              4-NDPA + p-NDPA                                 ______________________________________                                         0       2.3      89          1.5                                              50      3.5      73          0.99                                            150      6        63          0.62                                            300      9.75     12          0.23                                            500      14.7      3          0.05                                            ______________________________________                                    

Example 9

This example illustrates the effect that increasing the amount of basehas on yields of 4-NDPA and p-NDPA under conditions where the amount ofprotic material added to the reaction is kept constant.

Three identical reactions were run except that the amount oftetramethylammonium hydroxide dihydrate was varied in each. In a typicalreaction, aniline (2 mL), nitrobenzene (2 mL), water (100 μL) andtetramethylammonium hydroxide dihydrate (330 mg, 2.5 mmole) were mixedand allowed to react for 24 hours at room temperature in the air. Inthose cases where the solution showed large amounts of precipitates, anadditional 10 mL of aniline was added to solubilize the reaction beforesampling. All of these reactions were analyzed by HPLC.

                  TABLE 7                                                         ______________________________________                                        Volume   %       Grams   mMoles Yield (mmole)                                 Water Added                                                                            Water   Base    Base   4-NDPA + p-NDPA                               ______________________________________                                        100      4.3     0.330   2.5    0.05                                          100      5.9     0.660   5.0    0.15                                          100      9.6     1.65    12.5   1.24                                          ______________________________________                                    

Example 10

This example illustrates the reaction of aniline, nitrobenzene andtetramethylammonium hydroxide dihydrate under anaerobic conditions at50° C.

A 500 mL four-necked round-bottom flask equipped with a mechanicalstirrer, addition funnel, thermometer, and nitrogen inlet was chargedwith 90 mL of aniline., The aniline was purged with nitrogen andtetramethylammonium hydroxide dihydrate (54 g, 0.42 mole) was added inone portion. The reaction mixture was heated to 50° C. under a nitrogenblanket with stirring. Once the temperature in the reaction vesselreached 50° C., nitrobenzene (10 mL, 95 mmole) was added dropwise to thevigorously stirred mixture of aniline and base. The nitrobenzene wasadded at a rate such that the addition was complete within 30 minutes.The temperature of the reaction increased to 65° C. during thenitrobenzene addition. The reaction was allowed to stir for anadditional 90 minutes after which time it was analyzed by HPLC.Nitrobenzene conversion=100%. Yields based on nitrobenzene: p-NDPA(88.5%), 4-NDPA (4.3%) , phenazine (3.6%) , azobenzene (3.6%).

Example 11

This example illustrates that tetramethylammonium ion salt of 4-NDPA andp-NDPA can be produced in the method of the present invention.

Aniline (3.0 mL) was stirred with tetramethylammonium hydroxidedihydrate (330 mg, 2.5 mmole) in a controlled atmosphere dry box underargon. The aniline base mixture was filtered such that the aniline wasdelivered directly to 1 mL of nitrobenzene. Upon addition of theaniline-base solution, the reaction immediately turned red and aprecipitate began to form. The mixture was allowed to stir for 5 minutesafter which time the reaction was filtered. The red precipitate waswashed with several volumes of dry ether and allowed to dry. A portionof the solid was analyzed by ¹ H-NMR spectroscopy: (DMSO) δ3.1(s), 6.1(d, 1), 6.5 (t, 1), 6.6 (d,1), 6.76 (d, 1), 6.8 (t, 1), 7.04 (t, 1) 7.5(d,1). A drop of acetic acid-d₄ was added to the NMR tube which causedan immediate color change from red to yellow and the sample wasre-subjected to ¹ H-NMR spectroscopy. The resulting spectrum wasidentical to authentic 4-NDPA. A portion of the red solid was dissolvedin wet acetonitrile and subjected to HPLC analysis which indicated that4-NDPA was the major component.

Example 12

This example illustrates the conversion of 4-ADPA toN-(1,3-dimethylbutyl)-N'-phenyl-p-phenylenediamine, a useful antiozonantfor the protection of rubber products.

52 grams of 4-ADPA, prepared by the reaction of aniline and nitrobenzene(by the procedure of Example 1D), 100 grams methylisobutylketone (MIBK)and 0.3 grams of 3% platinum on carbon catalyst were charged into a oneliter Parr autoclave. After purging with hydrogen, the reaction mixturewas heated to 170°-175° C. and 800 psig hydrogen applied. The mixturewas reacted for 95 minutes and a sample withdrawn. GC analysis indicated0.4% unreacted 4-ADPA present. The reaction mixture was cooled andfiltered to remove catalyst and stripped to remove water and excessMIBK. The product, 71 grams, on cooling crystallized to a purplishsolid. Assay by GC internal standard method indicated 95.9% purity.

Similar reactions were conducted with similar results usingmethylisoamylketone and acetone.

The following examples utilized an improved HPLC analysis method. Theexternal standard method was used for the analysis of the couplingreaction products by HPLC. A Waters 600 series HPLC equipped with aVydac 201HS54 (4.6×250 mm) column and UV detection at 254 nm was used tomonitor all reactions

    ______________________________________                                        Elution Gradient                                                                                      % Solvent B                                           Time (min)                                                                             % Solvent A (Water)                                                                          (40% Methanol in ACN)                                 ______________________________________                                         0       75             25                                                    35       20             80                                                    40        0             100                                                   45        0             100                                                   46       75             25                                                    55       75             25                                                    ______________________________________                                    

External standards were prepared by dissolving N-methyl aniline(5.7 mg),nitrobenzene (13.0 mg), phenazine (4.5 mg), 4-nitrosodiphenylamine (68.1mg), 4-nitrodiphenylamine (7.2 mg), azobenzene (4.7 mg) and 25% aqueoussolution of tetramethylammoniumhydroxide (130 μL) in 50 mL ofacetonitrile. In the cases where aniline derivatives are used similarstandard solutions were generated.

Example 13

This example illustrates the continuous removal of water from thereaction of aniline, nitrobenzene and tetramethylammonium hydroxide(TMA(H)) by a vacuum distillation of the aniline/water azeotrope.

A 22 liter round bottom flask equipped with mechanical stirrer,Dean-Stark condenser, thermocouple, nitrobenzene addition line, andteflon baffle was charged with 15.1 lbs. of a 25% aqueous TMA(H)solution (6.70 L, 18.8 Moles TMA(H)). Water was removed by vacuumdistillation (55 torr) to the point where the base concentration was35%. During this step the reaction temperature rose steadily to a valuebetween 50°-55° C. Aniline (22.2 lbs, 9.88 L, 108 Mole) was charged intothe reactor and the vacuum distillation was continued at 55 torr. Waterand aniline were steadily removed as the azeotrope until the molar ratioof water to TMA(H) was 4:1. During this process the temperature of thereaction increased to 75° C. Once the appropriate molar ratio of waterto base was achieved, nitrobenzene (4.83 lbs., 1.79 L, 17.82 Mole) wasadded continuously over a period of three hours. During this additionwater and aniline are continuously being removed from the reaction byvacuum distillation at 55 torr. A good rate of water/aniline removal isto have the weight of the condensate removed equal the weight ofnitrobenzene added over the entire addition time. The reaction endpointcan be determined by HPLC analysis by monitoring the conversion ofnitrobenzene. Typical yields determined by HPLC analysis at 100%conversion of nitrobenzene: 4-nitrosodiphenylamine 92.1%,4-nitrodiphenylamine 3.4%, azobenzene 3.4%, and phenazine 0.9%.

Example 14

This example illustrates the use of various solvents in the reaction ofaniline, nitrobenzene and base to generate 4-ADPA intermediates.

To a solution containing 0.5 g (5.3 mmole) of aniline and 0.95 g (6.5mmole) of tetramethylammonium hydroxide dihydrate in 8 ml of solvent at70° C. under nitrogen, 0.65 g (5.3 mmole) of nitrobenzene was added viaa syringe. After the solution was stirred at 70° C. under nitrogen for12 hours the reaction was analyzed by HPLC with the results summarizedin Table 8.

                  TABLE 8                                                         ______________________________________                                               Nitro-                                                                        benzene   Phen-   Yield        Azo-                                    Solvent                                                                              Conversion                                                                              azine   4-NODPA 4-NDPA benzene                               ______________________________________                                        Toluene                                                                              99.5      0.64    76.4    20.9   1.5                                   Hexane 94.8      1.1     36.0    34.1   23.5                                  Ethylene                                                                             100       1.24    51.4    27     19.8                                  glycol di-                                                                    methyl                                                                        ether                                                                         Di-    50        0.9     45      4.3    0                                     isopropyl                                                                     ethyl                                                                         amine                                                                         ______________________________________                                    

Example 15

This example illustrates how a variety of different phase transfercatalysts can be employed in the reaction of aniline, nitrobenzene andbase to produce 4-ADPA intermediates.

In a typical reaction a three necked round bottom flask equipped withDean-Stark condenser was charged with 59 g (0.091 mole base) of aqueoustetrabutylammonium hydroxide and 55 g (0.59 mole) of aniline. Water wasremoved via azeotropic distillation with aniline 35 ml at 20 mmHg at 70°C. Nitrobenzene 1.2 g (0.091 mole) was introduced via a dropping funnelat 70° C. over 5 minutes. The reaction was stirred at 20 mmHg/70° C. for4 hours. The reaction was analyzed by HPLC with the results summarizedin Table 9.

In the case where bis-dibutylethyl hexamethylenediamine ammoniumhydroxide was used as base the reaction conditions were slightlydifferent. Thus 50 mL of the aqueous quaternary ammonium hydroxidesolution (0.0575 mmole hydroxide) was mixed with 200 mL of aniline. Thewater was removed by vacuum distillation at 67° C. until 28 mL of waterhad been distilled. Nitrobenzene (23.2 mmole, 2.85 g) was added dropwiseto the reaction under a nitrogen atmosphere at 50° C. The reaction wasallowed to stir for 2 hours after which time a sample was withdrawn foranalysis.

                                      TABLE 9                                     __________________________________________________________________________                  Nitrobenzene Yield %                                            Base          Conversion                                                                           Phenazine                                                                           4-NODPA                                                                             4-NDPA                                                                             Azobenzene                              __________________________________________________________________________    Tetrabutyl ammonium                                                                         77.5%  0     52.1  9.7  3.4                                     hydroxide                                                                     Tetrapropyl ammonium                                                                        100%   0.25  63.8  18.3 17.5                                    hydroxide                                                                     Choline hydroxide                                                                           83.6%  0.85  33.0  9.6  43.2                                    Benzyltrimethyl ammonium                                                                    100%   0.1   74.7  12.4 11.7                                    hydroxide                                                                     18-crown-6 + 2KOH                                                                           99.4%  0.33  77.8  11.5 6.54                                    Bis-dibutylethyl hexa-                                                                      85.3%  0     76    7    1.1                                     methylene diammonium                                                          hydroxide                                                                     __________________________________________________________________________

Example 16

This example illustrates how the addition of an external desiccant canbe used to absorb water in this reaction in replacement of theazeotropic distillation described in Example 13.

A 500 mL three necked round bottom flask equipped with mechanicalstirrer and Dean-Stark condenser was charged with 59.01 grams (0.162Mole base) of 25% aqueous tetramethylammonium hydroxide solution. Water(17 mL) was removed under vacuum distillation at 20 torr. Aniline (88.05grams) was added and 18 mL of water was removed under vacuum whichresults in a water to base molar ratio of 3:1. The distillation wasstopped and an appropriate desiccant was added. Nitrobenzene (19.18grams, 0.155 mole) was then added over one hour under a nitrogenblanket. During the addition the reaction temperature was maintained at70° C. The reaction was allowed to continue for one hour after theaddition of nitrobenzene was complete. The results of these experimentsare summarized in Table 10.

                                      TABLE 10                                    __________________________________________________________________________                     Nitrobenzene Yield %                                         Desiccant Grams Added                                                                          Conversion                                                                           Phenazine                                                                           4-NODPA                                                                             4-NDPA                                                                             Azobenzene                           __________________________________________________________________________    None      --     52.3%  0.34  46.7  2.0  1.0                                  Anhydrous Sodium                                                                        14.75  61.9%  0.50  58.6  2.2  0.8                                  Sulfate                                                                       4Å Molecular                                                                        28.1   78.2%  1.0   68.0  5.1  4.8                                  Sieves                                                                        __________________________________________________________________________

Example 17

This example illustrates how the amount of phenazine produced in thisreaction can be reduced by increasing the steric bulk of thetetraalkylammonium ion used as phase transfer catalyst. The experimentalprocedure used is identical to that described in Example 15. The resultsare summarized in Table 11.

                                      TABLE 11                                    __________________________________________________________________________                  Nitrobenzene Yield %                                            Base          Conversion                                                                           Phenazine                                                                           4-NODPA                                                                             4-NDPA                                                                             Azobenzene                              __________________________________________________________________________    Tetramethyl ammonium                                                                        100%   2.24  43    34   12.1                                    hydroxide                                                                     Tetrapropyl ammonium                                                                        100%   0.25  63.8  18.3 17.5                                    hydroxide                                                                     Benzyltrimethyl ammonium                                                                    100%   0.1   74.7  12.4 11.7                                    hydroxide                                                                     Tetrabutyl ammonium                                                                         77.5%  0     52.1  9.7  3.4                                     hydroxide                                                                     Phenyltrimethyl ammonium                                                                     48%   22    15    12   23                                      hydroxide                                                                     __________________________________________________________________________

Example 18

This example illustrates how various substituted aniline derivatives canbe employed in this reaction. The reactions were analyzed by HPLC andthe results are summarized in Table 12.

A) 3-Bromoaniline:

A solution of 10 ml (0.09 mole) of 3-bromoaniline and 1.5 g (0.01 mole)of tetramethylammonium hydroxide dihydrate was stirred at 70° C. undernitrogen. Nitrobenzene 0.9 ml (8.78 mole) was added dropwise via asyringe and the solution was stirred at 70° C. under nitrogen for 12hours.

B) 4-Nitroaniline:

A solution of (1.38 g, 0.01 mole) of 4-nitroaniline and 1.81 g (0.012mole) of tetramethylammonium hydroxide dihydrate in 3 ml ofdimethylsulfoxide was stirred at 70° C. under nitrogen. Nitrobenzene 1ml (0.01 mole) was added dropwise via a syringe and the solution wasstirred at 70° C. under nitrogen for 12 hours.

C) p-Toluidine:

A solution of (3 g,28 mmole) of p-toluidine and 0.9 g (6 mmole) oftetramethylammonium hydroxide dihydrate was stirred at 70° C. undernitrogen. Nitrobenzene 0.5 ml (5 mmole) was added dropwise via a syringeand the solution was stirred at 70° C. under nitrogen for 12 hours.

D) 4-Chloroaniline:

A solution of (4.8 g,0.03 mole) of 4-chloroaniline and 0.9 g (6 mmole)of tetramethylammonium hydroxide dihydrate in 2 ml of dimethylsulfoxidewas stirred at 70° C. under nitrogen. Nitrobenzene 0.71 g (5.6 mmole)was added dropwise via a syringe and the solution was stirred at 70° C.under nitrogen for 12 hours.

E) 4-Methoxyaniline:

A solution of 3 g (0.03 mole) of 4-methoxyaniline and 0.95 g (6 mole) oftetramethylammonium hydroxide dihydrate in 2 ml of dimethylsulfoxide wasstirred at 70° C. under nitrogen. Nitrobenzene (0.6 g,5 mmole) was addeddropwise via a syringe and the solution was stirred at 70° C. undernitrogen for 12 hours.

F) 2-Methoxyaniline:

A solution of (4.9 g,0.03 mole) of 2-methoxyaniline and 1.1 g (7.58mmole) of tetramethylammonium hydroxide dihydrate was stirred at 70° C.under nitrogen. Nitrobenzene 0.75 g (6.09 mmole) was added dropwise viaa syringe and the solution was stirred at 70° C. under nitrogen for 12hours.

                  TABLE 12                                                        ______________________________________                                                         Yield %                                                                  Nitrobenzene                                                                             4-NODPA    4-NDPA                                      Aniline Derivative                                                                        Conversion Derivative Derivative                                  ______________________________________                                        2-Methoxyaniline                                                                          100        55         44                                          4-Methoxyaniline                                                                          100        74         20                                          4-Chloroaniline                                                                            98        61          8                                          p-Toluidine 100        19          9                                          4-Nitroaniline                                                                             99         0         73                                          3-Bromoaniline                                                                            100        61          9                                          ______________________________________                                    

Example 19

This example illustrates how a variety of diamino nucleophiles willcouple to the para position of nitrobenzene.

Nitrobenzene (2 ml, 0.02 mole) was added via a syringe to a stirringsolution containing 1.08 g (0.01 mole) of 1,4-phenylenediamine, 3.6 g(0.02 mole) of tetramethylammonium hydroxide pentahydrate in 2 ml ofdimethylsulfoxide under nitrogen at 70° C. The solution was stirred atsuch condition for 4 hours. An aliquot was taken out for LC, MS, LC-MSanalyses. N,N'-(4-nitrosophenyl)-1,4-phenylenediamine,N-(4-nitrophenyl)-N'-(4-nitrosophenyl)-1,4-phenylenediamine andN,N'-(4-nitrophenyl)-1,4-phenylenediamine were obtained.

Other diamino nucleophiles such as 4,4'-methylenedianiline and2,4-diaminotoluene also give similar results under identical reactionconditions.

Example 20

This example illustrates the hydrogenation of 4-ADPA/tetramethylammonium (TMA) salt and 4-NDPA/TMA salt to 4-ADPA in various solvents.The hydrogenation reactions were carried out in a 300 cc stainless steelautoclave equipped with mechanical stirrer and temperature control.

A) 4-NODPA/TMA salt (12.4 grams, 0.0464 mmole) was charged into theautoclave with 150 mL of toluene. A 1% Pt/Carbon catalyst (300 mg dryweight) was added to the autoclave. The reactor was purged with nitrogenand then was placed under 200 psig hydrogen which was maintainedconstant throughout the hydrogenation. The reactions were stirred at1500 rpm and were allowed to attain a temperature of 80° C. Upon thetermination of hydrogen uptake the reaction was assumed to be complete.The material was removed and filtered to remove catalyst. The organiclayer was sampled and assayed by reverse phase HPLC which revealed 100%conversion of substrate and 97% yield of 4-ADPA.

B) A mixture of 4-NODPA/TMA salt (71 g, 262 mmole) and 4-NDPA/TMA salt(7 g, 24 mmole) was charged into the autoclave with 150 grams ofaniline. A 1% Pt/carbon catalyst was added (300 mg dry weight). Thereactor was purged with nitrogen and then was placed under 200 psighydrogen which was maintained constant throughout the reaction. Thereactions were stirred at 1500 rpm and were allowed to attain atemperature of 80° C. Upon the termination of hydrogen uptake thereaction was assumed to be complete. The material was removed andfiltered to remove catalyst. The organic layer was sampled and assayedby reverse phase HPLC which revealed 100% conversion of substrate and98% yield of 4-ADPA.

C) A mixture of 4-NODPA/TMA salt (36.5 g, 135 mmole) and 4-NDPA/TMA salt(3.4 g. 12 mmole) was charged into the autoclave with 51 grams of4-ADPA. A 1% Pt/carbon catalyst (300 mg dry weight) was added. Thereactor was purged with nitrogen and then was placed under 200 psighydrogen which was maintained constant throughout the reaction. Thereactions were stirred at 1500 rpm and were allowed to attain atemperature of 80% C. Upon the termination of hydrogen uptake thereaction was assumed to be complete. The material was removed andfiltered to remove catalyst. The organic layer was sampled and assayedby reverse phase HPLC which revealed 100% conversion of substrate andwith 4-ADPA being the only major product detected.

Example 21

This example illustrates the hydrogenation of 4-NODPA to 4-ADPA inaniline using a supported nickel catalyst.

Fifty grams of 4-NODPA, 200 grams aniline and 2.0 grams nickel onsilica-alumina support was charged into a one liter autoclave. Afterpurging to exclude oxygen, the mixture was heated to 80° C. and hydrogenfeed initiated at 200 mL/min. The feed was limited so that the maximumpressure was 280 psig. After 120 minutes the hydrogen flow indicatedthat the reaction was complete. A sample was withdrawn and analysisindicated 0.1% unreacted 4-NODPA remained. The product was 4-ADPA.

The preceding examples can be repeated with similar success bysubstituting the generically or specifically described solvents, basesand the like and/or operating conditions, such as other temperatures andpressures, of this invention for those used in the preceding examples.

From the foregoing description, one skilled in the art can easilyascertain the essential characteristics of this invention, and withoutdeparting from the spirit and scope thereof, can make various changesand modifications of the invention to adapt it to various usages andconditions.

What is claimed is:
 1. A method of producing one or more 4-ADPAintermediates comprising:a) bringing substituted aniline derivatives andnitrobenzene into reactive contact in a suitable solvent system; and b)reacting the substituted aniline derivatives and nitrobenzene in aconfined zone at a suitable temperature, and in the presence of asuitable base and a controlled amount of protic material to produce oneor more 4-ADPA intermediates.
 2. Method of claim 1 wherein said suitablesolvent system includes a solvent selected from aniline, nitrobenzene,dimethylsulfoxide, dimethylformamide, N-methylpyrrolidone, pyridine,toluene, hexane, ethylene glycol dimethyl ether, diisopropyl ethyl amineand mixtures thereof.
 3. Method of claim 2 wherein said solvent isselected from aniline, dimethylsulfoxide, dimethylformamide and toluene.4. Method of claim 2 wherein said suitable solvent system includes aprotic solvent.
 5. Method of claim 4 wherein said protic solvent isselected from methanol, water and mixtures thereof.
 6. Method of claim 1wherein said solvent system includes aniline and up to about 4 v/v %water based on the total volume of the reaction mixture.
 7. Method ofclaim 1 wherein said solvent system includes dimethylsulfoxide and up toabout 8 v/v % water based on the total volume of the reaction mixture.8. Method of claim 1 wherein said solvent system includes aniline and upto about 3 v/v % methanol based on the total volume of the reactionmixture.
 9. Method of claim 1 wherein said suitable temperature is fromabout -10° C. to about 150° C.
 10. Method of claim 1 wherein saidsuitable base is selected from organic and inorganic bases.
 11. Themethod of claim 10 wherein said organic and inorganic bases includealkali metals, alkali metal hydrides, alkali metal hydroxides, alkalimetal alkoxides, phase transfer catalysts in conjunction with a basesource, amines, crown ethers in conjunction with a base source andmixtures thereof.
 12. The method of claim 1 wherein said base isselected from an aryl ammonium, alkyl ammonium, aryl/alkyl ammonium, andalkyl diammonium salt in conjunction with a base source.
 13. The methodof claim 1 wherein said base is combined with substituted anilinederivative to form a mixture, which mixture is then brought intoreactive contact with nitrobenzene.
 14. The method of claim 1 whereinsaid substituted aniline derivative and nitrobenzene are combined toform a mixture to which the base is added.
 15. The method of claim 1wherein said solvent is aniline and said base is a tetraalkylammoniumhydroxide or an alkyl substituted diammonium hydroxide.
 16. The methodof claim 1 wherein said substituted aniline derivative and nitrobenzeneare reacted under aerobic conditions.
 17. The method of claim 1 whereinsaid substituted aniline derivative and nitrobenzene are reacted underanaerobic conditions.
 18. The method of claim 1 wherein the substituentof said substituted aniline derivatives is selected from the groupconsisting of halides, --NO₂, --NH₂, alkyl groups, alkoxy groups, --SO₃,--COOH and aryl, aralkyl or alkaryl groups containing at least one --NH₂group wherein halides are selected from the group consisting ofchloride, bromide and fluoride.
 19. The method of claim 18 wherein saidsubstituted aniline derivatives are selected from the group consistingof 2-methoxyaniline, 4-methoxyaniline, 4-chloroaniline, p-toluidine,4-nitroaniline, 3-bromoaniline, 3-bromo-4-aminotoluene, p-aminobenzoicacid, 2,4-diaminotoluene, 2,5-dichloroaniline, 1,4-phenylene diamine,4,4'-methylene dianiline and 1,3,5-triaminobenzene.
 20. A method ofproducing substituted derivatives of 4-aminodiphenylamine (4-ADPA)comprising:a) bringing substituted aniline derivatives and nitrobenzeneinto reactive contact in a suitable solvent system; b) reacting thesubstituted aniline derivatives and nitrobenzene in a confined zone at asuitable temperature, and in the presence of a suitable base andcontrolled amount of protic material to produce one or more 4-ADPAintermediates; and c) reducing the 4-ADPA intermediates under conditionswhich produce substituted derivatives of 4-ADPA.
 21. Method of claim 20wherein said suitable solvent system includes a solvent selected fromaniline, nitrobenzene, dimethylsulfoxide, dimethylformamide,N-methylpyrrolidone, pyridine, toluene, hexane, ethylene glycol dimethylether, diisopropyl ethyl amine and mixtures thereof.
 22. Method of claim21 wherein said solvent is selected from aniline, dimethylsulfoxide,dimethylformamide, toluene and mixtures thereof.
 23. Method of claim 21wherein said suitable solvent system includes a protic solvent. 24.Method of claim 23 wherein said protic solvent is selected frommethanol, water and mixtures thereof.
 25. Method of claim 20 whereinsaid solvent system includes aniline and up to about 4 v/v % water basedon the total volume of the reaction mixture.
 26. Method of claim 20wherein said solvent system includes dimethylsulfoxide and up to about 8v/v % water based on the volume of the reaction mixture.
 27. Method ofclaim 20 wherein said solvent system includes aniline and up to about 3v/v % methanol based on the volume of the reaction mixture.
 28. Methodof claim 20 wherein said suitable temperature is from -10° C. to about150° C.
 29. Method of claim 20 wherein said suitable base is selectedfrom organic and inorganic bases.
 30. The method of claim 29 whereinsaid organic and inorganic bases include alkali metals, alkali metalhydrides, alkali metal hydroxides, alkali metal alkoxides phase transfercatalysts in conjunction with a base source, amines, crown ether inconjunction with a base source and mixtures thereof.
 31. The method ofclaim 20 wherein said base is selected from an aryl ammonium, alkylammonium, aryl/alkyl ammonium and alkyl diammonium salt in conjunctionwith a base source.
 32. The method of claim 20 wherein said base iscombined with substituted aniline derivative to form a mixture, whichmixture is then brought into reactive contact with nitrobenzene.
 33. Themethod of claim 20 wherein said substituted aniline derivative andnitrobenzene are combined to form a mixture to which the base is added.34. The method of claim 20 wherein said solvent is aniline and said baseis a tetraalkylammonium hydroxide or an alkyl substituted diammoniumhydroxide.
 35. The method of claim 20 wherein said substituted anilinederivative and nitrobenzene are reacted under aerobic conditions. 36.The method of claim 20 wherein said substituted aniline derivative andnitrobenzene are reacted under anaerobic conditions.
 37. A method ofclaim 20 wherein said 4-ADPA intermediates are reduced utilizinghydrogen in the presence of a suitable catalyst.
 38. A method of claim37 wherein said catalyst is platinum on carbon, palladium on carbon ornickel.
 39. The method of claim 20 wherein the substituent of saidsubstituted aniline derivatives is selected from the group consisting ofhalides, --NO₂, --NH₂, alkyl groups, alkoxy groups, --SO₃, --COOH andaryl, aralkyl or alkaryl groups containing at least one --NH₂ groupwherein halides are selected from the group consisting of chloride,bromide and fluoride.
 40. The method of claim 39 wherein saidsubstituted aniline derivatives are selected from the group consistingof 2-methoxyaniline, 4-methoxyaniline, 4-chloroaniline, p-toluidine,4-nitroaniline, 3-bromoaniline, 3-bromo-4-aminotoluene, p-aminobenzoicacid, 2,4-diaminotoluene, 2,5-dichloroaniline, 1,4-phenylene diamine,4,4'-methylene dianiline and 1,3,5-triaminobenzene.
 41. A method ofproducing substituted derivatives of alkylated p-phenylenediaminescomprising:a) bringing substituted aniline derivatives and nitrobenzeneinto reactive contact in a suitable solvent system; b) reacting thesubstituted aniline derivatives and nitrobenzene in a confined zone at asuitable temperature, and in the presence of a suitable base andcontrolled amount of protic material to produce one or more 4-ADPAintermediates; c) reducing the 4-ADPA intermediates to producesubstituted derivatives of 4-ADPA; and d) reductively alkylating thesubstituted derivatives of 4-ADPA of Step (c).
 42. Method of claim 41wherein said suitable solvent system includes a solvent selected fromaniline, nitrobenzene, dimethylsulfoxide, dimethylformamide,N-methylpyrrolidone, pyridine, toluene, hexane, ethylene glycol dimethylether, diisopropyl ethyl amine and mixtures thereof.
 43. Method of claim42 wherein said solvent is selected from aniline, dimethylsulfoxide,dimethylformamide, toluene and mixtures thereof.
 44. Method of claim 42wherein said suitable solvent system includes a protic solvent. 45.Method of claim 44 wherein said protic solvent is selected frommethanol, water and mixtures thereof.
 46. Method of claim 42 whereinsaid solvent system includes aniline and up to about 4 v/v % water basedon the volume of the reaction mixture.
 47. Method of claim 42 whereinsaid solvent system includes dimethylsulfoxide and up to about 8 v/v %water based on the volume of the reaction mixture.
 48. Method of claim42 wherein said solvent system includes aniline and up to about 3 v/v %methanol based on the volume of the reaction mixture.
 49. Method ofclaim 42 wherein said suitable temperature is from about -10° C. toabout 150° C.
 50. Method of claim 42 wherein said suitable base isselected from organic and inorganic bases.
 51. The method of claim 50wherein said organic and inorganic bases include alkali metals, alkalimetal hydrides, alkali metal hydroxides, alkali metal alkoxides, phasetransfer catalysts in conjunction with a base source, amines, crownethers in conjunction with a base source and mixtures thereof.
 52. Themethod of claim 42 wherein said base is selected from an aryl ammonium,alkyl ammonium, aryl/alkyl ammonium and alkyl diammonium salt inconjunction with a base source.
 53. The method of claim 42 wherein saidbase is combined with substituted aniline derivatives to form a mixture,which mixture is then brought into reactive contact with nitrobenzene.54. The method of claim 42 wherein said substituted aniline derivativesand nitrobenzene are combined to form a mixture to which the base isadded.
 55. The method of claim 42 wherein said solvent is aniline andsaid base is a tetraalkylammonium hydroxide or an alkylsubstituteddiammonium hydroxide.
 56. The method of claim 42 wherein saidsubstituted aniline derivatives and nitrobenzene are reacted underaerobic conditions.
 57. The method of claim 42 wherein said substitutedaniline derivatives and nitrobenzene are reacted under anaerobicconditions.
 58. The method of claim 44 wherein said substitutedderivative of 4-ADPA is reductively alkylated utilizing a ketoneselected from the group consisting of acetone, methylisobutylketone,methylisoamylketone, and 2-octanone.
 59. The method of claim 41 whereinthe substituent of said substituted aniline derivatives is selected fromthe group consisting of halides, --NO₂, --NH₂, alkyl groups, alkoxygroups, --SO₃, --COOH and aryl, aralkyl or alkaryl groups containing atleast one --NH₂ group wherein halides are selected from the groupconsisting of chloride, bromide and fluoride.
 60. The method of claim 59wherein said substituted aniline derivatives are selected from the groupconsisting of 2-methoxyaniline, 4-methoxyaniline, 4-chloroaniline,p-toluidine, 4-nitroaniline, 3-bromoaniline, 3-bromo-4-aminotoluene,p-aminobenzoic acid, 2,4-diaminotoluene, 2,5-dichloroaniline,1,4-phenylene diamine, 4,4'-methylene dianiline and1,3,5-triaminobenzene.
 61. A method of producing one or more 4-ADPAintermediates comprising:a) bringing aniline or substituted anilinederivatives and nitrobenzene into reactive contact in a suitable solventsystem, b) reacting the aniline or substituted aniline derivatives andnitrobenzene in a confined zone at a suitable temperature, and in thepresence of a suitable base and protic material to produce one or more4-ADPA intermediates, and c) controlling the amount of said proticmaterial in step (a) or (b) to provide a yield of at least 33 molepercent of 4-ADPA intermediates based upon the limiting reagent used.62. The method of claim 61 wherein said suitable base is selected fromthe group consisting of tetrasubstituted ammonium hydroxides, alkylsubstituted diammonium hydroxides and mixtures thereof, wherein eachsubstituent of said tetrasubstituted ammonium hydroxide is independentlyselected from alkyl, aryl or arylalkyl groups.
 63. The method of claim62 wherein said suitable base is a tetrasubstituted ammonium hydroxide.64. The method of claim 63 wherein said tetrasubstituted ammoniumhydroxide is a tetraalkyl ammonium hydroxide.
 65. The method of claim 64wherein said tetraalkyl ammonium hydroxide is tetramethyl ammoniumhydroxide.
 66. The method of claim 62 wherein said suitable solvent isaniline.
 67. A method of producing one or more 4-ADPA intermediatescomprising:a) bringing aniline or substituted aniline derivatives andnitrobenzene into reactive contact in a suitable solvent system, and b)reacting the aniline or substituted aniline derivatives and nitrobenzenein a confined zone at a suitable temperature, and in the presence of asuitable base and protic material, wherein the amount of said proticmaterial is controlled to produce one or more 4-ADPAintermediates;provided that the protic material present during step (a)or (b), based on the amount of protic material charged plus the amountof protic material present in said aniline or substituted anilinederivatives, said nitrobenzene, said suitable solvent and said suitablebase, is at least 0.5 volume percent of the reaction mixture.
 68. Themethod of claim 67 wherein said suitable base is selected from the groupconsisting of tetrasubstituted ammonium hydroxides, alkyl substituteddiammonium hydroxides and mixtures thereof, wherein each substituent ofsaid tetrasubstituted ammonium hydroxide is independently selected fromalkyl, aryl or arylalkyl groups.
 69. The method of claim 68 wherein saidsuitable base is a tetrasubstituted ammonium hydroxide.
 70. The methodof claim 69 wherein said tetrasubstituted ammonium hydroxide is atetraalkyl ammonium hydroxide.
 71. The method of claim 70 wherein saidtetraalkyl ammonium hydroxide is tetramethyl ammonium hydroxide.
 72. Themethod of claim 67 wherein said suitable solvent is aniline.
 73. Amethod of producing one or more 4-ADPA intermediates comprising:a)bringing aniline or substituted aniline derivatives and nitrobenzeneinto reactive contact in a suitable solvent system; and b) reacting theaniline or substituted aniline derivatives and nitrobenzene in aconfined zone at a suitable temperature, and in the presence of asuitable base and a controlled amount of protic material to produce oneor more 4-ADPA intermediates,wherein said base is combined with saidaniline or substituted aniline derivative to form a mixture and saidnitrobenzene is added to said mixture at a controlled rate.
 74. Themethod of claim 73 wherein said suitable base is selected from the groupconsisting of tetrasubstituted ammonium hydroxides, alkyl substituteddiammonium hydroxides and mixtures thereof, wherein each substituent ofsaid tetrasubstituted ammonium hydroxide is independently selected fromalkyl, aryl or arylalkyl groups.
 75. The method of claim 74 wherein saidsuitable base is a tetrasubstituted ammonium hydroxide.
 76. The methodof claim 75 wherein said tetrasubstituted ammonium hydroxide is atetraalkyl ammonium hydroxide.
 77. The method of claim 76 wherein saidtetraalkyl ammonium hydroxide is tetramethyl ammonium hydroxide.
 78. Themethod of claim 74 wherein said suitable solvent is aniline.
 79. Themethod of claim 2 wherein said suitable solvent is selected from thegroup consisting of aniline, dimethylsulfoxide, N-methylpyrrolidone,dimethylformamide, pyridine, nitrobenzene and mixtures thereof.
 80. Themethod of claim 79 wherein said suitable solvent is aniline and saidsuitable base is selected from the group consisting of tetrasubstitutedammonium hydroxides, alkyl substituted diammonium hydroxides andmixtures thereof, wherein each substituent of said tetrasubstitutedammonium hydroxide is independently selected from alkyl, aryl orarylalkyl groups.
 81. The method of claim 1 wherein said suitable baseis selected from the group consisting of tetrasubstituted ammoniumhydroxides, alkyl substituted diammonium hydroxides and mixturesthereof, wherein each substituent of said tetrasubstituted ammoniumhydroxide is independently selected from alkyl, aryl or arylalkylgroups.
 82. The method of claim 81 wherein said suitable base is atetrasubstituted ammonium hydroxide.
 83. The method of claim 82 whereinsaid tetrasubstituted ammonium hydroxide is a tetraalkyl ammoniumhydroxide.
 84. The method of claim 83 wherein said tetraalkyl ammoniumhydroxide is tetramethyl ammonium hydroxide.
 85. A method of producingone or more 4-ADPA intermediates comprising:a) bringing aniline orsubstituted aniline derivatives and nitrobenzene into reactive contactin a suitable solvent system; and b) reacting the aniline or substitutedaniline derivatives and nitrobenzene in a confined zone at a suitabletemperature, and in the presence of a suitable base and a controlledamount of protic material to produce one or more 4-ADPAintermediates;wherein said suitable solvent is aniline, said proticmaterial is water and the amount of protic material present at thebeginning of the reaction is up to about 9.8 volume % water based on thetotal volume of the reaction mixture.